Imidazoles are a common component of a large number of natural products and pharmacologically active molecules. The prevalence and importance of this component makes methods which facilitate their preparation highly valuable. Despite intensive synthetic interest in these heterocycles during the past century, few methods have emerged which are general and capable of delivering highly functionalized imidazoles. In addition, many of the available methods utilize intermediates which are difficult to prepare, such as α-functionalized carbonyl and α-diamino compounds. One approach to imidazole synthesis involves cycloaddition of tosylmethyl isocyanides (TosMICs) to carbon-nitrogen double bonds. (See van Leusen et al J. Org. Chem. 1977, 42, 1153.)
The synthesis of imidazoles from TosMIC and imines is reported in Sisko et al.; J. Org. Chem. 2000, 65, 1515–24, “An Investigation of Imidazole and Oxazole Synthesis Using Aryl-Substituted TosMIC Reagents”.
See also U.S. Pat. No. 5,658,903 to Adams et al.; ten Have et al., Tetrahedron, 1997, Vol. 53, No. 33., pp. 11355–11368, “Novel Synthesis of 4(5)-Monosubstituted Imidazoles via Cycloaddition of Tosylmethyl Isocyanide to Aldimines”; Home et. al., Heterocycles, 1994, Vol. 39, No. 1, pp. 139–153, “A Two-Step Synthesis of Imidazoles From Aldehydes Via 4-Tosyloxazolines”; S. Marcaccini, Organic Preparations and Procedures Int., 1993, 25 (2), pp. 141–208, “The Use of Isocyanides in Heterocyclic Synthesis. A Review”; and N. Shih, Tetrahydron Letters, 1993, Vol. 34, No. 4, pp. 595–598, “Novel Synthesis of N-Unsubstituted Imidazoles Using N-Trimethylsilylimines” for other synthetic methods for preparing imidazoles.